Randomized controlled trials using electronic nicotine delivery systems as smoking cessation aids require an accurate, empirically-based understanding of the nicotine delivery profile of the products under study

Introduction

Randomized controlled trials (RCTs) are a mainstay for determining intervention efficacy and safety and have been used for decades to investigate the role of nicotine replacement in smoking cessation (1). Notably, cessation outcomes generally improve in a nicotine dose-related manner (2), highlighting the importance of drug delivery in intervention efficacy. Since 2013, a variety of reports describe RCTs that explore the efficacy and safety of electronic nicotine delivery systems (ENDS) for smoking cessation or reduction (3-11). One serious limitation shared by all of these RCTs is that the nicotine delivery profile of the ENDS product used was either uncertain (3,5-8,10,11) or minimal (4,9). Perhaps not surprisingly, then, cessation outcomes in many of these ENDS RCTs were modest (4-10). Results from rigorous laboratory research make clear that ENDS are a heterogeneous product class (12,13), and that ENDS nicotine emissions (i.e., yield) and user plasma nicotine concentration (i.e., delivery of nicotine to blood) are influenced by the interaction of device, liquid, and user behavior (14-19). To increase the likelihood of larger effect sizes, investigators planning ENDS RCTs likely would benefit from considering these factors.

ENDS device, liquid, and user behavior are critical for understanding ends nicotine yield and delivery

ENDS nicotine yield and delivery are a function of device power (14,15,17,18,20-22) and device construction (23,24) as well as liquid nicotine concentration (14-16,25,26) and propylene glycol/vegetable glycerin ratio (14,20,26-28). Moreover, because of differences in device characteristics, visual appearance (e.g., “tank” or “mod”) or device “type” (e.g., 1^st, 2^nd, or 3^rd generation) is not necessarily predictive of nicotine delivery (29,30). Therefore, choosing a device for an RCT based on its appearance or type is an unreliable method of assuring that nicotine will be delivered. Notably, several ENDS RCTs provide little information regarding the decision process used for selecting the ENDS products examined, apart from the appearance and/or popularity of the device. Also, user behavior, particularly puff duration, influences nicotine yield and delivery, with longer puffs leading to greater yield/delivery (14-16,31). Thus, even a device/liquid combination that appears to emit/deliver nicotine in controlled settings may fail to do so in an RCT if participants are not instructed regarding how to use it for maximum effectiveness.

One tool that is available to researchers planning an ENDS RCT is a mathematical model that predicts the nicotine emissions of any ENDS device/liquid combination based upon several factors including puff duration, liquid nicotine concentration and device power (15). This mathematical model explains 72% of the variability in ENDS’ rate of nicotine emissions (15) and so may be particularly useful in helping investigators select candidate ENDS devices and liquids for their RCT. For example, if investigators are interested in testing ENDSs that mimic the delivery profile of a combustible cigarette, the mathematical model will reveal which device/liquid combinations achieve cigarette-like nicotine yield in a given number of puffs of various puff durations (16). The nicotine delivery profile of those candidate products can then be determined using clinical laboratory methods.

There is a long tradition of using clinical laboratory methods to explore the nicotine delivery profile and other effects of tobacco products under controlled conditions (32-39). With some adaptation, these methods have revealed the considerable heterogeneity in ENDS nicotine delivery, with some products delivering little to no nicotine (40,41), others delivering some nicotine but dramatically underperforming a tobacco cigarette (31,42-47) and others meeting or exceeding the nicotine delivery of a tobacco cigarette after 10 puffs (18,29). Advantages of clinical laboratory methods are that they allow investigators to learn, in a single study, about how effectively various ENDS device/liquid combinations deliver nicotine to users’ blood under controlled and ad libitum puffing conditions; about how user behavior (i.e., puff duration) with those ENDS device/liquid combinations influences nicotine delivery; and about the acceptability of those ENDS device/liquid combinations as well as their ability to suppress tobacco/abstinence effects in smokers (17,48). Perhaps most important, relative to RCTs that often last multiple years and use between-group designs that often involve large samples [e.g., >500 people (7,10,11)] clinical laboratory studies can be rapid (i.e., 4–6 months) and use sensitive within-group designs involving 10–30 participants (16,17,42,45,48,49). Therefore, clinical laboratory studies can be a critical precursor for ensuring that an ENDS RCT involves products with known nicotine delivery profile(s) and can also help to inform RCT participants how their behavior will influence that profile (e.g., longer puffs increase nicotine delivery).

Ethical cessation-focused ENDS RCTs require knowing nicotine delivery profile

Many investigators likely would agree that an RCT involving a novel method of delivering a proven, systemically-active, life-saving medication should not go forward if the bioavailability of the drug administered via the new method is uncertain. In such a case, where participants have a life-threatening illness, where there is a proven treatment that requires delivery of the drug to the blood, and where the novel delivery system may not deliver the drug effectively, an RCT may risk the health of participants and also expend scarce resources unnecessarily. Determining the bioavailability of the drug using the new delivery method outside of an RCT might be a better first step. Cigarette smoking is lethal and investigators conducting RCTs testing cessation interventions must be mindful of participant health and resource conservation. Proven smoking cessation medications are available, including the drug nicotine that can be delivered efficaciously via several routes of administration. Why, then, would an investigator suggest and an ethics panel (e.g., investigational review board, or IRB) approve an RCT that involves nicotine-dependent, cigarette-smoking, treatment-seeking participants who are offered a proven medication (nicotine) using a method (ENDS) that may deliver no or very little of the drug?

A more rigorous approach would be for RCT investigators to make use of existing tools and empirically-validated, clinical laboratory methods that can be used to demonstrate ENDS nicotine delivery and also provide information regarding how participant behavior can influence nicotine delivery. IRBs can then be assured, as they should be, that the ENDS that will be used in the RCT is capable of delivering nicotine to RCT participants and that the ENDS nicotine delivery profile is at least similar to that of a nicotine replacement medication that has proven efficacy and safety.

Conclusions

ENDS have been called a “disruptive technology” (50) that some advocates believe “have the potential to end cigarette use” (51). This potential is more likely to be realized when policymakers, clinicians, and combustible cigarette smokers are guided by RCTs that investigate ENDSs that have been demonstrated to deliver nicotine effectively. If the nicotine delivery profile of ENDS products is uncertain, those products should not be included in an RCT that involves treatment-seeking cigarette smokers.

Acknowledgments

Funding: This work is supported by grant number F31DA047018 and U54DA036105 from the National Institute on Drug Abuse of the National Institutes of Health and the Center for Tobacco Products of the U.S. Food and Drug Administration. The content is solely the responsibility of the authors and does not necessarily represent the views of the NIH or the FDA.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editor (Michael Chaiton) for the series “Tobacco and Addiction” published in Journal of Public Health and Emergency. The article did not undergo external peer review.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/jphe-20-124). The series “Tobacco and Addiction” was commissioned by the editorial office without any funding or sponsorship. This research is supported by grant number U54DA036105 from the National Institute on Drug Abuse of the National Institutes of Health and the Center for Tobacco Products of the U.S. Food and Drug Administration. The content is solely the responsibility of the authors and does not necessarily represent the views of the NIH or the FDA. Not related to the current work, Dr. COC has received funding from Virginia Foundation for Healthy Youth and Virginia Commonwealth University Massey Cancer Center. The author has also received funds from University of Arkansas for Medical Sciences and Virginia Foundation for Healthy Youth for guest speaking and from NIH-Center for Scientific Review and California Tobacco-Related Disease Research Program for grant review. Dr. AJB has received funding for unrelated work from other state and federal agencies and foundations in the last 36 months. Additionally, Dr. AJB has received royalties for textbooks and consulting fees from the NIH and WHO, none of these are related to the funded project or research experiences this manuscript was based upon. Dr. AB has received funding for unrelated work from other state and federal agencies and foundations in the last 36 months. Additionally, Dr. AB has received payment from the NIH Center for Scientific Review; none of these are related to the funded project. Dr. TE is a paid consultant in litigation against the tobacco industry and also the electronic cigarette industry and is named on one patent for a device that measures the puffing behavior of electronic cigarette users and on another patent for a smartphone app that determines electronic cigarette device and liquid characteristics. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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